15-hydroxy-11-alpha-9-alpha-(epoxymethano)prosta-5-13-dienoic-acid and pimagedine

We investigated whether organ-specific differences exist in the role of inducible nitric oxide synthase (iNOS) in hyporeactivity to vasoconstrictors following 20 h in vitro exposure of isolated superior mesenteric, renal, hepatic and coronary arteries from the rat to bacterial lipopolysaccharide (LPS). LPS attenuated contraction in response to depolarizing KCl in all arteries. Maximum contractile responses to noradrenaline were attenuated in superior mesenteric and hepatic arteries, and those to the thromboxane A(2) analogue U46619 were attenuated in coronary arteries. LPS shifted the concentration-response curve to noradrenaline in renal arteries to the right. Removal of extracellular L-arginine improved the response to noradrenaline in superior mesenteric and renal arteries only. Addition of the iNOS inhibitor aminoguanidine resulted in full recovery of the responses to noradrenaline in superior mesenteric, renal and hepatic arteries. Contractile responses in coronary arteries did not improve after inhibition of iNOS activity. Therefore the pattern of the LPS-induced changes in vascular reactivity, as well as the contribution of iNOS to impaired vascular constriction, differed among vascular beds. These differences are likely to represent a contributory factor in the sepsis-associated redistribution of cardiac output.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Analysis of Variance; Animals; Arginine; Coronary Vessels; Dose-Response Relationship, Drug; Enzyme Inhibitors; Guanidines; Hepatic Artery; In Vitro Techniques; Lipopolysaccharides; Male; Mesenteric Artery, Superior; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Norepinephrine; Potassium Chloride; Rats; Rats, Wistar; Renal Artery; Shock, Septic; Vasoconstrictor Agents

The inducible isoform of nitric oxide synthase (iNOS) is expressed after systemic administration of lipopolysaccharide (LPS). The importance of expression of iNOS in blood vessels is poorly defined. Because nitric oxide from iNOS may alter vasomotor function, we examined effects of LPS on vasomotor function in carotid arteries from iNOS-deficient mice. We studied contraction of the carotid artery from wild-type and iNOS-deficient mice in vitro 12 h after injection of LPS (20 mg/kg ip). Contractile responses to PGF2alpha (3-30 microM) and thromboxane A2 analog (U-46619; 3-100 nM) were evaluated using vascular rings from mice treated with vehicle or LPS. Maximum force of contraction generated by rings in response to PGF2alpha was 0.39 +/- 0.02 and 0.25 +/- 0.01 (SE) g (n = 14) in vehicle and LPS-treated wild-type mice, respectively (P < 0.001 vs. vehicle). Thus LPS reduced constrictor responses in wild-type mice. Thiocitrulline and aminoguanidine (inhibitors of iNOS) improved contractile responses from LPS-treated wild-type vessels. Indomethacin also improved constrictor responses in arteries from wild-type mice injected with LPS. In contrast, contraction of the carotid arteries in response to PGF2alpha and U-46619 was not impaired in LPS-treated iNOS-deficient mice, and contraction was not altered by inhibitors of iNOS. Expression of iNOS mRNA was confirmed using RT-PCR in carotid arteries from wild-type mice after injection of LPS but not vehicle. PCR products for iNOS were not observed in iNOS-deficient mice. These findings provide the first direct evidence that iNOS mediates impairment of vascular contraction after treatment with LPS.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Carotid Arteries; Citrulline; Dinoprost; Enzyme Inhibitors; Gene Expression Regulation, Enzymologic; Guanidines; Heterozygote; In Vitro Techniques; Lipopolysaccharides; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle Contraction; Muscle, Smooth, Vascular; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; RNA, Messenger; Thiourea; Transcription, Genetic; Vasoconstriction